Although the importance of products of the prostaglandin (PG) G/H synthase (S) enzymes - colloquially known as cyclooxygenases (COXs) - in cardiovascular homeostasis has attracted much attention, little is known about the role of PGD2. This is the most abundant COX product of mast cells,but is also made by platelets, macrophages, endothelial and vascular smooth muscle cells (VSMCs) and lymphocytes. Although PGD2 can inhibit platelet function in vitro and has been suggested to contribute to resolution of inflammation, almost nothing is known of its importance in cardiovascular biology in vivo. One J ring metabolite, 15-deoxy delta(12,14)PGJ2 at high concentrations ligates PPARgamma ,inhibits IKKbeta and induces oapoptosis. PGD2 activates two receptors, DP1 and DP2 and endogenous concentrations of 15-deoxy delta(12,14) PGJ2 also activate the DP2. Both DPs are expressed in murine VSMCs and DP1 antagonism limits development of abdominal aortic aneurysmal (AAA). These translational studies are designed to investigate the role of PGD2 and related compounds in the response to vascular injury, combining genetic and pharmacological approaches in diverse models of injury in mice (wire injury, flow dependent remodeling, AAA, atherogenesis and the response to IPS) and humans (angioplasty, acute coronary syndrome and LPS administration). We shall utilize novel targeted lipidomic approaches to elucidate the role of COXs and PGD synthases in biosynthesis of these compounds under physiological conditions and in models of vascular injury in humans and in mice. Furthermore, we will elucidate the mechanism of niacin stimulated biosynthesis of PGD2 and the relevance of these products to the vascular response to niacin in humans. These studies will clarify the role of PGD2 and the diverse PCs formed from it in vascular biology, just as drugs targeting the PGDS enzymes and the DPs are being considered for clinical development. They elucidate the human pharmacology of niacin in conjunction with Project by Radar and integrate closely with study of the impact of variants in genes of this biosynthetic/response pathway in the phenotypes evoked in humans and described in Project by Reilly. It draws heavily on the lipidomic and proteomic resources of the Biomarker Core and utilizes the diverse models available through the Animal Model Core.